The long-term goal of our laboratory is to define the physiological mechanisms linking muscle blood flow to the metabolic state of the tissue, and how these mechanisms are altered under pathophysiological conditions. For example, obesity is associated with hypertension, dyslipidemia, and type II diabetes, a collection of conditions often referred to as metabolic syndrome affecting approximately 45 million US residents. Endothelial dysfunction is major component of metabolic syndrome. Impaired blood glucose homeostasis and elevated reactive oxygen species generation may be important factors in the endothelial dysfunction seen in these individuals. The present proposal employs an animal model, the obese Zucker rat which exhibits increased food consumption, and rapidly develops obesity, type II diabetes, and hypertension (i.e., metabolic syndrome). Thus, the Zucker rat provides a useful tool for the study of vascular function during a cohort of pathophysiological conditions that are rapidly growing in prevalence in western society. The experiments in this proposal will provide important new information concerning the cellular mechanism(s) of impaired functional hyperemia in a model of metabolic syndrome, and the cellular mechanisms by which exercise training improves endothelial function.